The goal of this project is to explore the relationship between sub-clinical intrauterine infection, preterm labor and the complications of prematurity. This year the Branch focused on establishing whether the human fetus can be affected by a systemic inflammatory response syndrome and the relationship between this condition and the onset of premature labor and perinatal morbidity. The following observations were made: 1) Definition of the "fetal inflammatory response syndrome": a fetal plasma IL-6 concentration of 11 pg/ml or more was used to defined the presence of a systemic inflammatory response in the human fetus. This condition was observed in approximately 20% of fetuses presenting with preterm labor and intact membranes and 45% of those presenting with preterm PROM. Importantly, 77.8% of fetuses affected with this syndrome develop severe morbidity after birth. Fetal plasma IL-6 concentration was an independent predictor of the occurrence of severe neonatal morbidity (odds ratio 4.3, 95% confidence interval 1-18.5) after adjustment for gestational age at delivery, amniotic fluid culture and other relevant variables. 2) The role of the human fetus in preterm parturition: To determine if the fetus plays a role in the onset of parturition, the relationship between the presence of a "fetal inflammatory response syndrome" and the subsequent onset of labor was studied in patients admitted with preterm PROM and who were not in labor. Fetuses affected by the syndrome had a higher rate of spontaneous preterm delivery within 24, 48, and 72 hours of the procedure than those without this syndrome (56% vs. 24%; 81% vs. 36% and 88% vs. 40%, respectively, p < 0.05 for each). Fetal plasma IL-6 was the only covariate significantly associated with the duration of pregnancy after adjusting for gestational age, amniotic fluid IL-6 and the microbiologic state of the amniotic cavity. These observations indicate that a systemic fetal cytokine response is associated with the impending onset of spontaneous preterm labor in patients with preterm PROM and therefore provide evidence for a role of the human fetus in determining the timing of preterm labor and delivery. 3) Expression of mRNA for anti-microbial peptides by the lower genital tract and gestational tissues: A crucial question is why some women develop an ascending intrauterine infection and others do not. Previous observations suggests that the cervical mucus which forms, the mucus plug during pregnancy, inhibits bacterial growth. The Branch provided evidence that chorionic tissue, endocervical tissue, endometrial tissue and an endometrial cell line, expressed mRNA for defensin 5, an epithelial anti-microbial peptide. The human placenta was also found to express defensin-1 (a hematopoietic defensin). These observations suggests that the expression of anti-microbial peptides may be a mechanism of host defense against ascending and transplacentally acquired infections.